rs999662

Variant names:

• chr16-56865596-T-G
• rs999662
• NM_001126108.2:c.282+79T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001126108.2(SLC12A3):​c.282+79T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0253 in 1,488,560 control chromosomes in the GnomAD database, including 620 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (71 hom., cov: 33)
  • Exomes 𝑓: 0.025 (549 hom.)
• Consequence: SLC12A3 NM_001126108.2 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.40
• Publications: 6 publications found

Genes affected

SLC12A3 (HGNC:10912): (solute carrier family 12 member 3) This gene encodes a renal thiazide-sensitive sodium-chloride cotransporter that is important for electrolyte homeostasis. This cotransporter mediates sodium and chloride reabsorption in the distal convoluted tubule. Mutations in this gene cause Gitelman syndrome, a disease similar to Bartter's syndrome, that is characterized by hypokalemic alkalosis combined with hypomagnesemia, low urinary calcium, and increased renin activity associated with normal blood pressure. This cotransporter is the target for thiazide diuretics that are used for treating high blood pressure. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

SLC12A3 Gene-Disease associations (from GenCC):

• Gitelman syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 16-56865596-T-G is Benign according to our data. Variant chr16-56865596-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1208183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0557 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A3	NM_001126108.2	c.282+79T>G		intron_variant	Intron 1 of 25	ENST00000563236.6	NP_001119580.2
SLC12A3	NM_000339.3	c.282+79T>G		intron_variant	Intron 1 of 25		NP_000330.3
SLC12A3	NM_001126107.2	c.282+79T>G		intron_variant	Intron 1 of 25		NP_001119579.2
SLC12A3	NM_001410896.1	c.282+79T>G		intron_variant	Intron 1 of 25		NP_001397825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A3	ENST00000563236.6	c.282+79T>G		intron_variant	Intron 1 of 25	1	NM_001126108.2	ENSP00000456149.2
SLC12A3	ENST00000438926.6	c.282+79T>G		intron_variant	Intron 1 of 25	1		ENSP00000402152.2
SLC12A3	ENST00000566786.5	c.282+79T>G		intron_variant	Intron 1 of 25	1		ENSP00000457552.1
SLC12A3	ENST00000262502.5	c.282+79T>G		intron_variant	Intron 1 of 25	5		ENSP00000262502.5

Frequencies

GnomAD3 genomes AF: 0.0279 AC: 4250 AN: 152180 Hom.: 71 Cov.: 33

Gnomad AFR AF: 0.0303

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0474

Gnomad ASJ AF: 0.0158

Gnomad EAS AF: 0.0468

Gnomad SAS AF: 0.0610

Gnomad FIN AF: 0.0144

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0214

Gnomad OTH AF: 0.0287

GnomAD4 exome AF: 0.0250 AC: 33385 AN: 1336262 Hom.: 549 AF XY: 0.0261 AC XY: 17450 AN XY: 669706

African (AFR) AF: 0.0304 AC: 953 AN: 31336

American (AMR) AF: 0.0445 AC: 1891 AN: 42460

Ashkenazi Jewish (ASJ) AF: 0.0142 AC: 359 AN: 25272

East Asian (EAS) AF: 0.0336 AC: 1305 AN: 38870

South Asian (SAS) AF: 0.0587 AC: 4859 AN: 82786

European-Finnish (FIN) AF: 0.0181 AC: 688 AN: 38100

Middle Eastern (MID) AF: 0.0274 AC: 146 AN: 5330

European-Non Finnish (NFE) AF: 0.0214 AC: 21722 AN: 1015574

Other (OTH) AF: 0.0259 AC: 1462 AN: 56534

GnomAD4 genome AF: 0.0280 AC: 4264 AN: 152298 Hom.: 71 Cov.: 33 AF XY: 0.0293 AC XY: 2179 AN XY: 74480

African (AFR) AF: 0.0305 AC: 1267 AN: 41564

American (AMR) AF: 0.0474 AC: 725 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0158 AC: 55 AN: 3472

East Asian (EAS) AF: 0.0469 AC: 243 AN: 5178

South Asian (SAS) AF: 0.0615 AC: 297 AN: 4830

European-Finnish (FIN) AF: 0.0144 AC: 153 AN: 10614

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0214 AC: 1456 AN: 68012

Other (OTH) AF: 0.0284 AC: 60 AN: 2116

Alfa AF: 0.0222 Hom.: 19

Bravo AF: 0.0281

Asia WGS AF: 0.0500 AC: 174 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 02, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.24
DANN	Benign	0.65
PhyloP100		-2.4
PromoterAI		-0.019	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs999662; hg19: chr16-56899508;